Osteoporosis is mainly a disease of elderly women, who have low cancellous and cortical bone mass, poor bone structure, and fragility fractures. Though osteoporosis can be prevented by maintaining "peak" bone mass, treating it by substantially increasing bone strength is difficult. We propose using osteopenic, aged female rats to test a two-phase concept to treat established osteopenia. Since it has an anabolic phase to restore lost bone and a maintenance phase to preserve the new bone, it is named Activate->Restore->Maintain (A->R->M). We propose two experiments using aged female rats with established osteopenia originating from estrogen-depletion or chronic disuse, or a combination of the two. We will use either prostaglandin E2 (PGE2) or parathyroid hormone (hPTH) as anabolic agents to restore lost bone (+Phase). Past experience with both shows that their discontinuation is associated with rapid disappearance of the new bone they induce. When we stop +Phase, we will switch to an agent known chiefly for its ability to block bone loss (+Phase). We will use either 17-beta-estradiol (E2) or risedronate, a bisphosphonate. We will study animals at the beginning of +Phase, at the close of +Phase, and twice during +Phase, to establish both the permanence of the new bone and its incorporation into the adult skeleton by modeling and remodeling processes. A third experiment examines the ability of co-treatment with a resorption inhibitor and an anabolic agent, to add new bone, yet avoid an early transient phase of bone loss. For endpoints, we plan quantitative histologic studies of bone mass, structure, and turnover in the cancellous bone of the proximal and distal tibial metaphyses, and cortical bone of the tibio-fibular junction. We hypothesize that bone mass of the osteopenic skeleton improves during treatment with an anabolic agent, and then is permanently maintained by other routinely available agents. We hypothesize that differences in estrogen-depletion and disuse-related osteopenia exist, such that risedronate can, but E2 cannot, maintain new bone in the skeleton of an animal suffering chronic disuse osteopenia. We hypothesize that co- treating with a resorption inhibitor allows anabolic agents to work normally, while blocking the consequences of any early resorption phase. A->R->M, that limits the use of skeletal anabolic agents to the time when they are most effective, could hasten the application of such agents for treating osteoporosis.